The CD40-CD40 ligand (CD40L) interaction is known to be essential for humoral immune responses. It has also been recently suggested that CD40 on antigen presenting cells play an important role in T cell activation. To elucidate a role of CD40 in T cell activation/differentiation, we studied immune responses of CD40-deficient mice against Leishmania major, a resolution of which is known to be dependent on a Th1 T cell response. Our results demonstrated that CD40-deficient mice were susceptible to L.major infection.Furthermore, it turned out that the mutant mice mounted a Th2 response to the parasites instead of a Th1 response because of an absence of CD40-dependent IL-12 production by antigen-presenting cells. The role of CD40 in generation of effector T cells could be demonstrated in vitro. T cells from OVA-specific TCR transgenic mice were stimulated with OVA peptides in the presence of CD40-positive or negative APC.Certain concentrations of peptides could induce generation of IFN-g producing Th1 cells in the presence of CD40-positive APC but not in the presence of CD40-negative APC while IL-4 producing Th2 cells could be induced by both CD40-positive and CD40-negative APC with appropriate concentrations of peptides. Moreover, addition of IL12 could rescue the generation of Th1 cells in the presence of CD40-negative APC.These results suggest that CD40-dependent IL-12 production by APC may be critical in generation of Th1 effector cells.